A variety of immune factors influence the susceptibility of CD4 T cells to HIV-1 infection, including soluble factors and the state of T cell differentiation. Evidence for the importance of these host factors includes the observation that lymphocytes from different donors are not equally infectable with HIV-1, raising the possibility that resistance of lymphocytes to HIV I infection in vitro might be associated with different rates of disease progression (Spira, A. I. and D. D. Ho. 1995. J. Virol. 69:422; and Wainberg, M. A., N. Blain, and L. Fitz-Gibbon. 1987. Clin. Exp. Immunol. 70:136). Host factors that are recognized to affect the susceptibility of CD4 cells to HIV infection include factors intrinsic to the CD4 cell and indirect factors. Among the direct factors of recognized importance are CD4 and fusion coreceptors(s) expression. The density of CD4 receptors expressed on the cell surface influences the efficiency of HIV-1 infection (Kabat, D., 1994. J. Virol. 68:2570; and Brand, D., 1995. J. Virol. 69:166). Recently chemokine receptors have been identified as a critical determinant of susceptibility to infection with HIV-1. Macrophage-tropic strains of HIV-1 utilize CCR5 as a fusion cofactor (Alkhatib, G., 1996, Science 272:1955; Doranz, B. J., 1996 Cell 85:1149; Choe, H., 1996. Cell 85:1135; Dragic, T., 1996. Nature 381: Deng, H., 1996. Nature 381:661) while T cell tropic strains of HIV-1 employ CXCR4/fusin as a coreceptor (Feng, Y., 1996. Science 272:872). The importance of these coreceptors is illustrated by the recent observation that some multiply exposed individuals who remain uninfected with HIV-1 have mutations in CCR5 (Liu, R., 1996. Cell 86:367; Dean, M., 1996. Science 273:1856).
Indirect factors may also be important in determining the resistance of CD4 cells to HIV-1 infection. Most of the described effects have depended on CD8 cells. Levy and coworkers first reported that CD8 T cells from HIV-infected individuals were capable of suppressing endogenous viral replication at a transcriptional level in CD4 T cells from HIV-infected individuals (Walker, C. 1986. Science 234:1563). Suppression was mediated by a non-cytolytic, MHC-nonrestricted mechanism (Mackewicz, C. E., 1995. Proc. Natl. Acad. Sci. U.S.A. 92:2308). The C—C chemokines RANTES, MIP-1α, MIP-β have been shown to inhibit infection of M-tropic isolates, but not T cell tropic strains of HIV-1 (Cocchi, F., 1995. Science 270:1811). The potential importance of these findings were underscored by a report from Paxton and coworkers indicating that CD4 cells from people who were repeatedly exposed to HIV but remain uninfected, were resistant to infection with HIV (Paxton, W. A., 1996. Nat. Med. 2:412). They found that these resistant individuals secreted higher levels of C—C chemokines in vitro. Multiple distinct HIV-1 suppressive activities appear to be secreted or shed by CD8 cells (Barker, T. D., 1996. J. Immunol. 156:4476). IL-2 and IL-16 have also been proposed to inhibit HIV replication via CD8 cell mediated mechanisms (Kinter, A. L., 1995. Proc. Natl. Acad. Sci. U.S.A. 92:10985; Baier, M., A. 1995. Nature 378:563). IL-10 and TGF-β have also been shown to have inhibitory effects on HIV-1 replication (Fauci, A. S. 1996. Nature 384:529).
Recent studies have shown that while specificity of T cell activation is dictated by antigen receptor signals, effective activation requires at least one costimulatory signal. CD28 is the dominant costimulatory signal, and interaction of CD28 with its counter receptors CD80 or CD86 is required for the induction of many cellular immune responses (June, C. H., 1994. Immunol. Today 15:321). We recently reported that CD28 stimulation could mediate an antiviral effect (Levine, B. L., 1996. Science 272:1939). The effect was potent as CD4 cells from HIV-infected donors could be routinely propagated in culture without virus replication in the absence of antiretroviral drugs. The CD28-mediated effect was distinguished from previous reports in that the inhibition acted early in the viral life cycle and appeared to be independent of CD8 T cells.